Diminished NADPH transhydrogenase activity and mitochondrial redox regulation in human failing myocardium |
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Authors: | Freya L Sheeran Jan Rydström Mikhail I Shakhparonov Nikolay B Pestov Salvatore Pepe |
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Institution: | 1. Department of Surgery, Monash University Faculty of Medicine, Alfred Hospital, Melbourne, Australia;2. Heart Research, Critical Care & Neuroscience, Murdoch Children''s Research Institute, Royal Children''s Hospital and the Department of Pediatrics, University of Melbourne, Melbourne, Australia;3. Biochemistry and Biophysics, Department of Chemistry, University of Gothenburg, Göteborg, Sweden;4. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia |
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Abstract: | Although the functional role of nicotinamide nucleotide transhydrogenase (Nnt) remains to be fully elucidated, there is strong evidence that Nnt plays a critical part in mitochondrial metabolism by maintaining a high NADPH-dependant GSH/GSSG ratio, and thus the control of cellular oxidative stress. Using real-time PCR, spectrophotometric and western blotting techniques, we sought to determine the presence, abundance and activity level of Nnt in human heart tissues and to discern whether these are altered in chronic severe heart failure. Left ventricular levels of the NNT gene and protein expression did not differ significantly between the non-failing donor (NF) and heart failure (HF) group. Notably, compared to NF, Nnt activity rates in the HF group were 18% lower, which coincided with significantly higher levels of oxidized glutathione, lower glutathione reductase activity, lower NADPH and a lower GSH/GSSG ratio. In the failing human heart a partial loss of Nnt activity adversely impacts NADPH-dependent enzymes and the capacity to maintain membrane potential, thus contributing to a decline in bioenergetic capacity, redox regulation and antioxidant defense, exacerbating oxidative damage to cellular proteins. |
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